title: HDAC2 phosphorylation-dependent Klf5 deacetylation and RARα acetylation induced by RAR agonist switch the transcription regulatory programs of p21 in VSMCs.
abstract: Abnormal proliferation of vascular smooth muscle cells (VSMCs) occurs in hypertension, atherosclerosis and restenosis after angioplasty, leading to pathophysiological vascular remodeling. As an important growth arrest gene, p21 plays critical roles in vascular remodeling. Regulation of p21 expression by retinoic acid receptor (RAR) and its ligand has important implications for control of pathological vascular remodeling. Nevertheless, the mechanism of RAR-mediated p21 expression in VSMCs remains poorly understood. Here, we show that, under basal conditions, RARα forms a complex with histone deacetylase 2 (HDAC2) and Krüppel-like factor 5 (Klf5) at the p21 promoter to inhibit its expression. Upon RARα agonist stimulation, HDAC2 is phosphorylated by CK2α. Phosphorylation of HDAC2, on the one hand, promotes its dissociation from RARα, thus allowing the liganded-RARα to interact with co-activators; on the other hand, it increases its interaction with Klf5, thus leading to deacetylation of Klf5. Deacetylation of Klf5 facilitates its dissociation from the p21 promoter, relieving its repressive effect on the p21 promoter. Interference with HDAC2 phosphorylation by either CK2α knockdown or the use of phosphorylation-deficient mutant of HDAC2 prevents the dissociation of Klf5 from the p21 promoter and impairs RAR agonist-induced p21 activation. Our results reveal a novel mechanism involving a phosphorylation-deacetylation cascade that functions to remove the basal repression complex from the p21 promoter upon RAR agonist treatment, allowing for optimum agonist-induced p21 expression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang 050017, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Shu
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Li
authors.forename: Sui-Bing
authors.initials: SB
authors.lastname: Miao
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.forename: Hui-Jing
authors.initials: HJ
authors.lastname: Shi
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.forename: Jin-Kun
authors.initials: JK
authors.lastname: Wen
mesh_terms: D000107:Acetylation; D000818:Animals; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; C492215:Klf5 protein, rat; D051741:Kruppel-Like Transcription Factors; D046912:Multiprotein Complexes; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D047390:Casein Kinase II; C533426:Hdac2 protein, rat; D056464:Histone Deacetylase 2